Method of making antipyrine



NI' r p ERNEST F. GRETHERAND zrosnrn 1. BELsLnYgor MIDLAND, MICHIGAN, essrenons no THE now cnnmroanconrnnx, or MIDLAND, gmionrenn, A ooarom rron or MICHIGAN No Drawing. Application filed July 19,

This invention relates to improvements in the manufacture of 1-phenyl-2,3-d1methyl- 5-pyrazolon, commonly known as antipyrlne.

The usual method employed consists in re-' 5 acting between. acetoacetic ester and phenyl hydrazine, forming 1-phenyl-3-methyl-5-pyrazolon, which has the structural formula:

Eve have found that other alkyl halides, as for example ethyl bromide, when dissolved in methyl alcohol, can be used in place of the more expensive methyl iodide, and that when so used the methyl group alone is substituted in the pyrazolon nucleus rather than the alkyl group of the halide employed in the reaction. This constitutes a valuable improvement 1n the process in hand, to the accomplishment whereof the invention consists of the steps so hereinafter fully described and particularly pointed out in the claims, the following description setting forth one preferred mode of procedure. a I

Although antipyrine has been known for many years, this compound being characterized by the attachmentof a methyl group (CH in the second N'position, no one, so far as we are aware, hasever succeeded in introducing any other group into the same 40 position. In our experience with other alkyl halides, such as allyl' bromide or ethyl bromide, in attempting to introduce a different alkyl group, no definite product was obtained when working with a solvent such as ethyl or allyl alcohol, benzol, or the like. Apparently only the methyl group was capable of attaching itself to the free N position by means of the usual methods of alkylat1on. Following negative results in this direction, we employed methyl alcohol as the solvent,

vmrnon or. ivmxruonu'rrrxnmn Y 1928. Serial in. 294,055. I

with ethyl bromide-as the 'alkyl compound. Contrary to our previous experience, we found that a reaction took place readily and smoothly, and the product obtained was, surprisingly, antipyrine in very good yield. In other words, the methyl group, derivedffrom the methyl alcohol solvent, was joined 'tothe free N positiominstead of the ethyl group mally *havebeen expected. The reaction is illustrated the equation:

ter of indiflerence if it is dissolved in me thyl alcohol. Thisifeature is of great value in that it permits of the useof whatever alkyl halide is most advantageous from the standpoint of cost, ease of handling, etc. In m.

tice we prefento use ethyl'bromide which is moderate in cost as compared with alkyl iodides, and, beinga liquid at ordinary temperature, is more conveniently handled than the highly volatile methyl bromide.

As a specific exampleofthe application of our improved method33 methyl-5-pyrazolon, obtained in the usual manner hereinbefore referred to, and 31 parts of ethyl bromide are dissolved in 64 parts of methyl alcohol. The solution is heated in an autocleave at a temperature between 100 and 130 0., preferably 120 (3., for 10 to 20 hours, with stirring. The reaction mixture is then discharged by any suitable means for the rea lease of pressure, and the solvent distilled off.

The residue consisting of the hydrobromide salt is treated with sodium carbonate to liberate the free base,which is extracted from the aqueous mixture with chloroform. After distilling off the solvent, the crude antipyrine is purified by the usual methods. The yield of purified product is in excess of 90 per cent.

Other modes of applying the principle of our invention may be employed .nswmmon parts of 1-phenyl-3- 7 instead of the ofthealkyl halide employed, as would nor-- Y ill one explained, change being made as regards the method herein disclosed, provided the step or steps stated by any of the following claims or the equivalent of such stated step or steps be employed.

We therefore particularly point out and distinctly claim as our invention:

1. In a method of the character described, methylating an aryl-pyrazolon by reacting thereon with methyl alcohol and an alkyl halide whose alkyl radical contains at least two carbon atoms.

2. The method of making antipyrine, which comprises reacting between 1-phenyl-8 methyl-5-pyrazolon and ethyl bromide in methyl alcohol solution.

3. In a method of the character described,

methylating 1-phenyl-3-methyl-5-pyrazolon by reacting thereon with methyl alcohol and an alkyl halide whose alkyl radical contains at least two carbon atoms.

4. The method of making antipyrine which comprises heating 1-phenyl-3-methyl- 5-pyrazolon with methyl alcohol and ethyl bromide under pressure at a temperature between 100 and 130 C.

5. In a method of the character described, methylating 1-phenyl-3-methyl-5-pyrazolon by reacting thereon with methyl alcohol and an alkyl bromide whose alkyl radical contains at leasttwo carbon atoms.

6. In a method of the character described, methylating l-phenyl-3-methyl-5-pyrazolon by reacting thereon under pressure at a tem perature of between approximately 100 and 130 C. with methyl alcohol and an alkyl bromide whose alkyl radical contains at least two carbon atoms.

Signed by us this 13th dayoit July, 1928.

ERNEST F. GRETHER. JOSEPH P. BELSLEY. 

